TiCl4-catalyzed indirect anti-Markovnikov hydration of alkynes: Application to the synthesis of benzo[b]furans

Article abstract of DOI:10.1021/jo070887i

(Chemical Equation Presented) An efficient methodology for the indirect anti-Markovnikov hydration of unsymmetrically substituted terminal and internal alkynes is based on TiCl₄-catalyzed hydroamination reactions. Its application to ortho-alkynylhaloarenes, followed by a copper-catalyzed O-arylation, provides flexible access to substituted benzo[b]furans.

Full text of DOI:10.1021/jo070887i

TiCl -Catalyzed Indirect Anti-Markovnikov Hydration of Alkynes:
4
Application to the Synthesis of Benzo[b]furans
Lutz Ackermann*,†,‡ and Ludwig T. Kaspar‡
Institut f u¨ r Organische und Biomolekulare Chemie, Georg-August-UniVersitaet Goettingen, Tammannstr. 2,
D-37077 Goettingen, Germany, and Department of Chemistry and Biochemistry,
Ludwig-Maximilians-UniVersitaet Muenchen, Butenandtstrasse 5-13, D-81377 Muenchen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
ReceiVed April 27, 2007
An efficient methodology for the indirect anti-Markovnikov hydration of unsymmetrically substituted
terminal and internal alkynes is based on TiCl -catalyzed hydroamination reactions. Its application to
4
ortho-alkynylhaloarenes, followed by a copper-catalyzed O-arylation, provides flexible access to substituted
benzo[b]furans.
Introduction
protocol for highly selective anti-Markovnikov hydration reac-
tions of internal alkynes has proven elusive. An overall, indirect
hydration of an alkyne is accomplished through a sequence
The regioselective functionalization of unsymmetrically
substituted alkynes is of fundamental importance in synthetic
6
consisting of a regioselective hydroamination and the subsequent
hydrolysis of the generated imine.
1
organic chemistry. The hydration of carbon-carbon triple
bonds provides direct access to substituted ketones and alde-
7
8
Pioneering studies on zirconium- and titanium-catalyzed
2
hydes. Traditionally, toxic mercury(II) compounds were em-
9
hydroamination reactions of alkynes set the stage for the
ployed for the addition of water to alkynes, yielding the
corresponding Markovnikov products.1 Similar regioselec-
tivities were accomplished through the use of expensive late
transition-metal catalysts.2 Hydration reactions with excellent
anti-Markovnikov selectivities were achieved for terminal
alkynes with ruthenium-based catalysts.2 However, a general
development of more elaborate titanium-based hydroamination
-3
10,11
catalysts.
We on the contrary felt attracted by the possibility
of employing inexpensive TiCl4 as precatalyst for preparatively
,4
12
useful intermolecular hydroamination reactions of alkynes.
,5,6
(5) (a) Tokunaga, M.; Wakatsuki, Y. Angew. Chem., Int. Ed. 1998, 37,
867-2869. (b) Suzuki, T.; Tokunaga, M.; Wakatsuki, Y. Org. Lett. 2001,
, 735-737. (c) Tokunaga, M.; Suzuki, T.; Koga, N.; Fukushima, T.;
2
3
†
Georg-August-Universitaet Goettingen.
Ludwig-Maximilians-Universitaet Muenchen.
Horiuchi, A.; Wakatsuki, Y. J. Am. Chem. Soc. 2001, 123, 11917-11924.
(d) Wakatsuki, Y.; Hou, Z.; Tokunaga, M. Chem. Rec. 2003, 3, 144-157.
(e) Grotjahn, D. B.; Incarvito, C. D.; Rheingold, A. L. Angew. Chem., Int.
Ed. 2001, 40, 3884-3887. (f) Grotjahn, D. B.; Lev, D. A. J. Am. Chem.
Soc. 2004, 126, 12232-12233. (g) Grotjahn, D. B. Chem.-Eur. J. 2005,
11, 7146-7153. (h) Alvarez, P.; Bassetti, M.; Gimeno, J.; Mancini, G.
Tetrahedron Lett. 2001, 42, 8467-8470. (i) Chevallier, F.; Breit, B. Angew.
Chem., Int. Ed. 2006, 45, 1599-1602. (j) Labonne, A.; Kribber, T.;
Hintermann, L. Org. Lett. 2006, 8, 5853-5856.
‡
(1) (a) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int.
Ed. 2004, 43, 3368-3398. (b) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem.
ReV. 2004, 104, 3079-3159.
(
2) (a) Hintermann, L.; Labonne, A. Synthesis 2007, 1121-1150. (b)
Tani, K.; Kataoka, Y. In Catalytic Heterofunctionalization; Togni, A.,
Gr u¨ tzmacher, H., Eds.; Wiley-VCH: Weinheim, 2001; pp 171-216.
(3) For selected recent examples of the use of strong Brønsted acids,
see: (a) Le Bras, G.; Provot, O.; Peyrat, J.-F.; Alami, M.; Brion, J.-D.
Tetrahedron Lett. 2006, 47, 5497-5501. (b) Tsuchimoto, T.; Joya, T.;
Shirakawa, E.; Kawakami, Y. Synthesis 2000, 1777-1778 and references
therein.
(6) Oestreich, M. Sci. Synth. 2007, 25, 199-211.
(7) (a) Walsh, P. J.; Hollander, F. J.; Bergman, R. G. J. Am. Chem. Soc.
1988, 110, 8729-8731. (b) Walsh, P. J.; Baranger, A. M.; Bergman, R. G.
J. Am. Chem. Soc. 1992, 114, 1708-1719. (c) Duncan, A. P.; Bergman, R.
G. Chem. Rec. 2002, 2, 431-445.
(
4) Selected examples: (a) Meier, I. K.; Marsella, J. A. J. Mol. Catal.
1
993, 78, 31-42. [Au]: (b) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka,
(8) For a first titanium-catalyzed intermolecular hydroamination of an
alkyne, see: (a) Hill, J. E.; Profilet, R. D.; Fanwick, P. E.; Rothwell, I. P.
Angew. Chem., Int. Ed. Engl. 1990, 29, 664-665. See also: (b) McGrane,
P. L.; Jensen, M.; Livinghouse, T. J. Am. Chem. Soc. 1992, 114, 5459-
5460. (c) McGrane, P. L.; Livinghouse, T. J. Org. Chem. 1992, 57, 1323-
1324. (d) Polse, J. L.; Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc.
1998, 120, 13405-13414.
M. Angew. Chem., Int. Ed. 2002, 41, 4563-4565. (c) Fukuda, Y.; Utimoto,
K. J. Org. Chem. 1991, 56, 3729-3731. [Pt]: (d) Hiscox, W.; Jennings, P.
W. Organometallics 1990, 9, 1997-1999. (e) Hartman, J. W.; Hiscox, W.
C.; Jennings, P. W. J. Org. Chem. 1993, 58, 7613-7614. [Rh]: (f) Blum,
J.; Huminer, H.; Alper, H. J. Mol. Catal. 1992, 75, 153-160. [Ir]: (g)
Hirabayashi, T.; Okimoto, Y.; Saito, A.; Morita, M.; Sakaguchi, S.; Ishii,
Y. Tetrahedron 2006, 62, 2231-2234 and references therein.
(9) A review: Pohlki, F.; Doye, S. Chem. Soc. ReV. 2003, 32, 104-114.
1
0.1021/jo070887i CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/13/2007
J. Org. Chem. 2007, 72, 6149-6153
6149

Ackermann and Kaspar
TABLE 1. Indirect TiCl4-Catalyzed Hydration of Alkynesa
hydrolysis
method
isolated
yield (%)
ratio
2/3
2
R1
Ph
Ph
Ph
Ph
Ph
n-Hex
n-Hex
n-Hex
n-Hex
n-Hex
n-Hex
n-Hex
i-Pr
b
entry
R NH2
1
2
3
4
5
6
7
8
9
t-BuNH2
CyNH2
(1a)
(1a)
(1a)
(1a)
(1a)
(1b)
(1b)
(1b)
(1b)
(1b)
(1b)
(1b)
(1c)
(1d)
(1b)
(8)c
84
93
A
B
A
A
A
A
A
B
B
A
B
A
A
PhMeCHNH2
sec-BuNH2
n-OctNH2
n-BuNH2
n-OctNH2
sec-BuNH2
PhMeCHNH2
MesCH2NH2
PhNH2
MesNH2
PhNH2
PhNH2
PhNH2
78
66
84
80
d
d
55/45
54/46
56/44
64/36
86/14
91/9
98/2
82/18
2/98
d
86
80
94
92
82
91
10
11
12
13
14
15
e
t-Bu
n-Hex
78
-
f
a
2
Reaction conditions: (a) 1 (1.0 mmol), R NH2 (1.0 mmol), TiCl4 (20 mol %), t-BuNH2 (1.2 mmol), PhMe (2 mL), 22 h, 105 °C. (b) Hydrolysis
b
1
methods: A: SiO2, CH2Cl2, 20 °C. B: aqueous HCl (2 N), 20 °C. Isolated yields refer to mixtures of regioisomeric products. Mes ) 1,3,5-Me3C6H2.
NMR analysis. GC conversion. 170 °C. 150 °C. Without t-BuNH2.
H
c
d
e
f
SCHEME 1. TiCl
4
-Catalyzed Anti-Markovnikov Hydroamination with Subsequent Reduction
Given the practical importance of efficient and economical
ketone synthesis, we wished to make use of our protocol for
regioselective indirect hydration reactions of internal alkynes.
Herein, we report on the development of an operationally simple
and regioselective yet efficient indirect anti-Markovnikov hydra-
tion of alkynes and its application to the synthesis of benzo[b]-
furans.
developed protocol had thus far been only applied to intermo-
lecular hydroaminations with aniline and hydrazine derivatives
1
2,13
(Table 1).
While t-BuNH2 gave only a sluggish conversion
of an internal alkyne (entry 1), we were pleased to observe that
other alkyl amines proved to be viable substrates for TiCl4-
catalyzed intermolecular hydroamination reactions (entries 2-4).
Notably, challenging n-alkyl-substituted amines1 could be
converted in high yields as well (entries 5-7). However, more
selective anti-Markovnikov hydrations of internal and terminal
alkynes were accomplished when using more sterically hindered
amines (entries 6-12). Hence, synthetically useful regioselec-
tivities could be obtained with aniline derivatives, giving rise
to anti-Markovnikov hydration products (entries 11 and 12) or,
after reduction, to the corresponding secondary amines (Scheme
1). Alkynes bearing a primary or secondary alkyl substituent
yielded the anti-Markovnikov indirect hydration products with
high regioselectivities (entries 11-13). On the contrary, alkyne
0f
Results and Discussion
At the outset of our studies, we explored TiCl4-catalyzed
hydroamination reactions with alkyl amines, as our previously
(10) Selected recent examples: (a) Buil, M. L.; Esteruelas, M. A.; Lopez,
A. M.; Mateo, A. C.; Onate, E. Organometallics 2007, 26, 554-565. (b)
Swartz, D. L., II; Odom, A. L. Organometallics 2006, 25, 6125-6133. (c)
Smolensky, E.; Kapon, M.; Eisen, M. S. Organometallics 2005, 24, 5495-
5
2
498. (d) Tillack, A.; Khedkar, V.; Jiao, H.; Beller, M. Eur. J. Org. Chem.
005, 5001-5012. (e) Hoover, J. M.; Petersen, J. R.; Pikul, J. H.; Johnson,
A. R. Organometallics 2004, 23, 4614-4620. (f) Heutling, A.; Pohlki, F.;
Doye, S. Chem.-Eur. J. 2004, 10, 3059-3071. (g) Zhang, Z.; Schafer, L.
L. Org. Lett. 2003, 5, 4733-4736. (h) Lorber, C.; Choukroun, R.; Vendier,
L. Organometallics 2004, 23, 1845-1850. (i) Shi, Y.; Ciszewski, J. T.;
Odom, A. L. Organometallics 2001, 20, 3968-3969. (j) Johnson, J. S.;
Bergman, R. G. J. Am. Chem. Soc. 2001, 123, 2923-2924 and references
therein.
1
d with a tertiary alkyl substituent required harsher reaction
conditions and gave, likely because of steric interactions, the
Markovnikov product predominantly (entry 14). Importantly,
no conversion of alkyne 1b was achieved in the absence of
t-BuNH2 (entry 15), highlighting its importance as precursor to
an amido ligand as well as for the formation of catalytically
(
11) For review articles, see: (a) Odom, A. L. Dalton Trans. 2005, 225-
2
33. (b) Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2003, 935-946.
(
Ackermann, L.; Born, R. Tetrahedron Lett. 2004, 45, 9541-9544. (c)
Ackermann, L.; Kaspar, L. T.; Gschrei, C. J. Chem. Commun. 2004, 2824-
825.
12a
active titanium imido species. The amines can be potentially
12) (a) Ackermann, L. Organometallics 2003, 22, 4367-4368. (b)
(13) Abbiati, G.; Casoni, A.; Canevari, V.; Nava, D.; Rossi, E. Org. Lett.
2006, 8, 4839-4842.
2
6150 J. Org. Chem., Vol. 72, No. 16, 2007

Indirect Anti-MarkoVnikoV Hydration of Alkynes
TABLE 2. Indirect Hydration of ortho-Alkynylhaloarenes 1a
a
3
Reaction conditions: (a) 1 (1.0 mmol), R NH2 (1.0-1.3 mmol), TiCl4 (20 mol %), t-BuNH2 (1.2 mmol), PhMe (2 mL), 22 h, 105 °C. (b) Hydrolysis:
b
1
H NMR analysis. c 170 °C. (a) 1 (1.0
d
aqueous HCl (2 N), 20 °C. Isolated yields refer to mixtures of regioisomeric products. Mes ) 1,3,5-Me3C6H2.
mmol), R NH2 (1.0 mmol), TiCl4 (20 mol %), t-BuNH2 (1.2 mmol), PhMe (2 mL), 22 h, 120 °C. (b) Aqueous HCl (2 N), 100 °C.
3
1
4
recovered through an acidic workup procedure (entries 3, 9,
and therefore it continues to induce extensive synthetic efforts.
1
5
10, and 12), rendering the overall approach atom economical.
Recently, intramolecular copper-catalyzed O-arylations of
enolates with aryl iodides and bromides were elegantly used to
The benzo[b]furan motif is an essential substructure in a large
number of natural and unnatural biologically active compounds,
1
6
access the benzo[b]furan scaffold.
J. Org. Chem, Vol. 72, No. 16, 2007 6151

Ackermann and Kaspar
TABLE 3. Copper-Catalyzed Benzo[b]furan Synthesisa
a
Reaction conditions: 2 (0.7 mmol), K3PO4 (1.4 mmol), CuI (10 mol %), L (30 mol %), DMF (2 mL), 105 °C, 22 h; yields of isolated products. b GC
conversion.
Consequently, we applied the TiCl4-catalyzed indirect hydra-
terminal alkynes, employing both aryl and alkyl amines. With
aryl amines highly selective anti-Markovnikov selectivities were
achieved. The power of our protocol was illustrated with its
application to an efficient benzo[b]furan synthesis.
tion protocol to ortho-alkynylhaloarenes (Table 2). Simple
anilines proved valuable for regioselective indirect hydration
reactions of alkyl-(hetero)aryl-substituted alkynes (entries 2 and
4
-8). To achieve preparatively useful selectivities with diaryl-
substituted alkynes, the use of a sterically hindered aniline
Experimental Section
proved beneficial (entries 9-16).
Finally, we used ketones 2 as starting materials for a copper-
catalyzed benzo[b]furan synthesis (Table 3). Substrates bearing
bromide substituents as leaving groups could be cyclized without
stabilizing ligand (entries 1-4). Importantly, the protocol proved
not only applicable to aryl bromides, but also to less reactive
4
Representative Procedure for the TiCl -Catalyzed Indirect
Hydration of Alkynes, 1-Phenyloctan-2-one (Table 1, Entry 12).
t-BuNH (0.130 mL, 1.20 mmol) was added to a solution of TiCl
2
4
2
(0.022 mL, 0.20 mmol, 20 mol %) in toluene (2 mL) under N .
Mesitylamine (0.135 g, 1.00 mmol) and 1b (0.186 g, 1.00 mmol)
were added. The solution was stirred at 105 °C for 22 h. At ambient
temperature, aqueous HCl (2 N, 10 mL) was added, and the reaction
chlorides. Here, most efficient catalysis was achieved with Me2-
NCH2CO2H17 as ligand (entries 5-10).
mixture was stirred at 20 °C for 24 h. H
and the separated aqueous phase was extracted with Et
mL). The combined organic layers were dried over MgSO
concentrated in vacuo. The remaining residue was purified by
column chromatography on silica gel (n-pentane/Et O, 30/1) to yield
-phenyloctan-2-one (167 mg, 82%, purity: 98% by H NMR and
2
O (50 mL) was added,
O (3 × 60
and
In conclusion, we reported on TiCl4-catalyzed indirect hydra-
tion reactions of unsymmetrically substituted internal and
2
4
(
14) For a recent review, see: Cacchi, S.; Fabrizi, G.; Goggiamani, A.
Curr. Org. Chem. 2006, 10, 1423-1455 and references therein.
15) For related palladium-catalyzed transformations, see: (a) Watanabe,
2
1
1
(
1
GC analysis) as a yellow oil. H NMR (300 MHz, CDCl ) δ )
3
M.; Yamamoto, T.; Nishiyama, M. Angew. Chem., Int. Ed. 2000, 39, 2501-
2
4
2
504. (b) Willis, M. C.; Taylor, D.; Gillmore, A. T. Org. Lett. 2004, 6,
755-4757. (c) Willis, M. C.; Taylor, D.; Gillmore, A. T. Tetrahedron
006, 62, 11513-11520. (d) Anderson, K. W.; Ikawa, T.; Tundel, R. E.;
7.35-7.20 (m, 5H), 3.68 (s, 2H), 2.44 (t, J ) 7.4 Hz, 2H), 1.55 (tt,
J ) 7.1, 7.1 Hz, 2H), 1.31-1.24 (m, 6H), 0.87 (t, J ) 6.6 Hz,
13
3
H). C NMR (75 MHz, DEPT, CDCl
3
) δ ) 209.0 (CO), 134.8
), 42.4 (CH ),
), 14.4 (CH ). IR
Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 10694-10695.
(C
q
), 129.8 (CH), 129.1 (CH), 127.3 (CH), 50.5 (CH
2
2
(16) (a) Chen, C.-y.; Dormer, P. G. J. Org. Chem. 2005, 70, 6964-
3
(
1.9 (CH
2
), 29.2 (CH
2
), 24.1 (CH
2
), 22.9 (CH
2
3
6
967. (b) Carril, M.; SanMartin, R.; Tellitu, I.; Dominguez, E. Org. Lett.
ATR): 2955, 2928, 2858, 1709, 1496, 1454, 698 cm 1. MS (EI)
-
2
006, 8, 1467-1470.
+
(
17) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164-5173.
m/z (relative intensity) 204 (1) [M ], 113 (100), 91 (44), 85 (37),
6152 J. Org. Chem., Vol. 72, No. 16, 2007

Indirect Anti-MarkoVnikoV Hydration of Alkynes
6
2
5 (11), 57 (17), 43 (100). HR-MS (EI) m/z calcd for C14
04.1514, found 204.1528.
H
20
O
1.82 (tt, J ) 7.5, 7.5 Hz, 2H), 1.50-1.37 (m, 6H), 1.00-0.95 (m,
3H). 13C NMR (75 MHz, DEPT, CDCl
) δ ) 159.8 (C ), 154.6
(C ), 129.0 (C ), 123.0 (CH), 122.3 (CH), 120.1 (CH), 110.7 (CH),
101.7 (CH), 31.6 (CH ), 28.9 (CH ), 28.4 (CH ), 27.7 (CH ), 22.6
(CH ), 14.0 (CH ). IR (ATR): 2954, 2928, 2858, 1602, 1588, 1454,
3
q
Representative Procedure for Cu-Catalyzed Benzo[b]furan
Synthesis, 2-n-Hexylbenzo[b]furan (4a) (Table 3, Entry 1).
PO (0.293 g, 1.38 mmol) and CuI (0.013 g, 0.07 mmol, 10 mol
) were added to a solution of 2a (0.195 g, 0.69 mmol) in DMF
2 mL) under N . The solution was stirred at 105 °C for 22 h. At
ambient temperature, brine (60 mL) and Et O (60 mL) were added
to the reaction mixture. The separated aqueous phase was extracted
with Et
O (2 × 60 mL). The combined organic layers were dried
over MgSO and concentrated in vacuo. The remaining residue was
q
q
2
2
2
2
K
%
(
3
4
2
3
-
1
1253, 1167, 792, 749, 738 cm . MS (EI) m/z (relative intensity)
+
2
202 (23) [M ], 145 (5), 131 (100), 107 (5), 95 (12), 77 (6). HR-
2
MS (EI) m/z calcd for C14H18O 202.1358, found 202.1335.
Acknowledgment. Support by Sanofi-Aventis, the DFG, the
Fonds der Chemischen Industrie, the Dr. Otto R o¨ hm Ged a¨ cht-
nisstiftung, the R o¨ mer Foundation, and DuPont is gratefully
acknowledged.
2
4
purified by column chromatography on silica gel (n-pentane) to
yield 4a (114 mg, 82%) as a colorless liquid. The spectral data are
in accordance with those reported in the literature.1 H NMR (300
8 1
Supporting Information Available: Additional experimental
MHz, CDCl
3
) δ ) 7.57-7.54 (m, 1H), 7.51-7.47 (m, 1H), 7.31-
1
13
procedures, characterization data, as well as H and C NMR
spectra for all products. This material is available free of charge
via the Internet at http://pubs.acs.org.
7.22 (m, 2H), 6.45-6.44 (m, 1H), 2.84 (dt, J ) 7.5, 0.9 Hz, 2H),
(18) Kabalka, G. W.; Wang, L.; Pagni, R. M. Tetrahedron 2001, 57,
8
017-8028.
JO070887I
J. Org. Chem, Vol. 72, No. 16, 2007 6153